FIELD OF THE INVENTION
The present invention is directed towards amorphous rimonabant and processes for the preparation thereof.
BACKGROUND OF THE INVENTION
Rimonabant having structural formula-I is chemically known as 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-,Y-(piperidin-l-yl)pyrazole- 3-carboxamicle.
(Figure Removed)
Rimonabant is a selective antagonist of cannabinoid typel (CBO receptor and a new class of compounds that target a potential treatment for obesity, smoking cessation. Alzheimer's disease, Parkinson's disease etc. The drug, formulated as 20 mg film coated tablets, is typically given once daily to the patients.
Rimonabant was first disclosed in U.S. Patent No. 5, 624.941, and is still under FDA review to approve for marketing in US. In a method described in U.S. Patent No. 5,624,941, crude rimonabant was purified by column chromatography. and the concentrated desired fractions were crystallized from isopropyl ether while in another exemplified process, the product was crystallized from methyl cyclohexane to give purified rimonabant.
Recently, two novel crystalline forms of rimonabant, referred to as forms I and II, were characterized and described in U.S. patent application 2005/0043356. According to this application, the method claimed in U.S. Patent No. 5,624,941 allows the preparation of rimonabant in crystalline form-1.
Yet another novel crystalline form III of rimonabant free base is characterized and disclosed in our co-pending Application No. 2530/DEL/2006.
The discovery of new amorphous forms of active pharmaceutical ingredients ("APIs") provides opportunities to improve the performance characteristics of a pharmaceutical product. Generally, amorphous solids offer opportunities for solubility and bioavailability enhancement since these materials are more soluble than the crystalline form of the same compound. The rate of dissolution is also a consideration in formulating syrups, elixirs and other liquid medicaments.
None of the prior art references discussed above disclose amorphous form of rimonabant. Thus, there is a widely recognized need for developing stable amorphous form of Rimonabant, which would further offer advantages over crystalline forms in terms of better dissolution and the availability profiles.
The present invention provides amorphous rimonabant and processes for the preparation thereof.
SUMMARY OF THE INVENTION
The invention is directed to amorphous rimonabant
Preferably, the amorphous rimonabant is characterized by an X-ray diffraction pattern, substantially as depicted in Figure 1
The amorphous rimonabant of the invention is preferably prepared in a process, comprising converting any other crystalline form of rimonabant to amorphous rimonabant.
The amorphous rimonabant of the invention is also preferably prepared in a process, comprising providing a solution of rimonabant in a solvent selected from the group consisting of acyclic ethers, halogenated hydrocarbons, alkyl nitriles, a CY,s ketones. aromatic hydrocarbons and mixtures thereof, or evaporating and removing the solvent by distillation optionally under vacuum as well as at atmospheric pressure.
The solvent is preferably selected from the group consisting of tetrahydrofuran, clichloromethane, chloroform, acetonitrile, acetone, toluene and mixtures thereof,
Amorphous rimonabant of the invention is also preferably prepared in a process comprising providing a solution of rimonabant in a solvent, and removing the solvent by rapid vacuum evaporation under a pressure of less than about 760 mm Hg and a temperature of less than about 100°C. The pressure is preferably less than about 100 mm Hg. and, more preferably, less than about 70 mm Hg. The temperature is preferably about 20°C to about 80°C, and, more preferably, between 30°C to 60°C. Preferably, the concentration and solvent of the solution, and the temperature, vacuum and feeding rate of the rapid vacuum evaporation are such that the rimonabant precipitates substantially instantly.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 illustrates the powder X-ray diffraction pattern for amorphous rimonabant. Figure 2 illustrates the infrared spectra of amorphous rimonabant.

DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed towards amorphous form of 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-niethyl-A?-(piperidin-l-yl)-l//-pyrazole-3-carboxamide (rimonabant) and processes for preparing the same. The rimonabant free base used to prepare the amorphous form of the present invention may be prepared according to conventional methods known in the art such as the processes described in prior art or as claimed in our co-pending Application No. 253 1/DEL/2006. As used herein, "ambient temperature" refers to a room temperature, usually at a temperature of about 18 to about 25°C, preferably about 20 to about 22°C.
Amorphous form of rimonabant encompassed by the present invention may be characterized by at least one of Karl Fisher or TGA, IR spectroscopy, X-Ray power diffraction (XRD), or differential scan calorimetry (DSC) techniques.
The water content of the amorphous form of rimonabant of the present invention is between 0.01% and 0.5 % by weight of amorphous form of rimonabant, typically between 0.3 and 0.4 % by weight of amorphous form of rimonabant as determined by Karl Fisher titration .
The amorphous form of rimonabant, herein designated as amorphous rimonabant, is characterized by having broad X-ray diffraction spectrum as shown in figure I.
The amorphous rimonabant, is further characterized by infrared spectrum having peaks at about 3455, 2938, 2855, 1681, 1530, 1497, 1383, 1358, 1246, 1138, 1092. 1012, 969, 833 and 815 crrf'as identified by figure IT. Tt can further be characterized by melting point range of about 100-121°C.
The X-ray diffraction patterns of amorphous rimonabant are measured on a PANalytical X'Pert Pro diffractometer with Cu radiation and expressed in terms of
two-theta, d-spacings and relative intensities. One of ordinary skill in the art understands that experimental differences may arise due to differences in instrumentation, sample preparation, or other factors.
All infrared measurements are made on Perkin Elmer Spectrum 100 spectrometer using KBr pellets having the characteristic absorption bands expressed in reciprocal centimeter.
Melting point was conducted using a Polmon MP Apparatus MP 96 with a sample weight of about 10 mg.
Another embodiment of the invention provides processes for preparing the above amorphous rimonabant.
The amorphous rimonabant of the invention is preferably prepared in a process, comprising providing a solution of rimonabant in a suitable solvent selected from the group consisting of cyclic ethers, halogcnated hydrocarbon, alkyl nitrile, a CY,, aliphatic ketones, aromatic hydrocarbon, and mixtures thereof, for a time sufficient to convert to amorphous rimonabant and recovering the same. The solvent is preferably selected from the group consisting of, tetrahydrofuran, dichloromethane. chloroform, acetonitrile, acetone, toluene and the like.
Typically, the rimonabant is dissolved in a suitable solvent at a temperature of about 10-35°C, preferably at ambient temperature rill a clear solution is obtained, 'Ihc solvent is then removed by conventional techniques known in the prior art like distillation, preferably vacuum distillation is employed at a temperature of about 35-60°C to yield amorphous rimonabant in exceptionally high purity and yields.
The rimonabant taken as starting material in the present invention could be any of the polymorphic form I, III or any other form or mixture thereof. Preferably the starting material is rimonabant form I.
Yet another embodiment of the invention provides processes for converting amorphous form of the present invention to polymorphic form I of rimonabant. The form I of rimonabant is preferably prepared in a process, comprising a solution of amorphous rimonabant in a suitable solvent for a time sufficient to convert to form I. filtering and isolating polymorphic-ally pure form I. the solvent can he selected from the group consisting of. but limited to hydrocarbons, water, ethers and the like. Preferably isopropyl ether, n-hexaue and cyclobexane are used.
Typically, the amorphous form of rimonabant is suspended in a solvent and the suspension is stirred for a time sufficient to convert to form I. Preferably the suspension is stirred for a period of about 30 minutes to few hours, more preferably the solution is stirred for a period of about 30-60 minutes. Preferably the suspension is stirred is conducted at ambient temperature. The solid form 1 so obtained can be recovered by conventional physical separation such as filtration and extraction from the reaction mixture. Preferably the precipitates are filtered and optionally washed with same solvent. The filtered material, a semi-dry powder, is further dried to remove surface solvents in a vacuum tray drier, tray drier, fluid bed drier or a rotary vacuum drier or suck dried. Preferably, material is suck dried at about 30°C to about 60°C for a period of about 4 hours to 6 hours to afford polymorphically pure form I of rimonabant.
The present invention is advantageous as it converts any known form of rimonabant to pure amorphous form only. The product prepared by the process is chemically stable. The process is simple, economically viable.
Having described the invention with reference to certain preferred embodiments. other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the preparation of the composition and methods of use of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
EXAMPLES
Example 1
Preparation of Amorphous Rimonabant
Rimonabant Form I (5.0 g) was stirred in methylene dichloride (25 ml) at ambient temperature till a clear solution is obtained. The solvent was distilled off completely at 30-40°C to give 4.90 g of amorphous rimonabant.
Example 2
Preparation of Amorphous Rimonabant
Rimonabant Form I (5.0g) was stirred in tetrahydrofuran (25 ml) at ambient temperature till a clear solution is obtained. The solvent was distilled off completely at 40-50°C to give 4.90 g of amorphous rimonabant.
Example 3
Preparation of Amorphous Rimonabant
Rimonabant Form I (5.0 g) was stirred in acetonitrile (100 ml) at ambient temperature till a clear solution is obtained. The solvent was distilled off completely at 60-65°C to give 4.82 g of amorphous rimonabant.
Example 4
Preparation of Amorphous Rimonabant
Rimonabant Form I (5.0 g) was stirred in toluene (25 ml) at ambient temperature till a clear solution is obtained. The solvent was distilled off completely at 60-65°C to give 4.9 g of amorphous rimonabant.
Example 5
Preparation of Amorphous Rimonabant
Rimonabant Form I (5,0 g) was stirred in acetone (50 ml) at ambient temperature till a clear solution is obtained. The solvent was distilled off completely at 35-40°C to give 4.90 g of amorphous rimonabant.
Example 6
Conversion of Amorphous Rimonabant to Rimonabant Form I
Amorphous rimonabant (5.0 g) was stirred in n-hexane (25 ml) at ambient temperature for 30 minutes. The solid was collected by filtration and washed with n-hexane (5 ml) and dried at 45°C for 5 hours to give 4.65 g of Rimonabant Form 1,
Example 7
Conversion of Amorphous Rimonabant to Rimonabant Form I
Amorphous rimonabant (5.0 g) was stirred in cyclohexane (25 ml) at ambient temperature for 30 minutes. The solid was collected by filtration and washed with cyclohexane (5 ml) and dried at 45°C for 5 hours to give 4.80 g of Rimonabant Form I.

WE CLAIM
1. Amorphous rimonabant having a powder X-ray diffraction pattern
substantially as depicted in Fig. 1.
2. Amorphous rimonabant characterized by infrared spectrum having peaks at
about 3455, 2938, 2855, 1681, 1530, 1497, 1383, 1358, 1246, 1138, 1092,
1012, 969, 833 and 815 cm'1 and as identified by Fig 2.
3. Amorphous rimonabant of claim 1 containing up to about 0.5 % water.
4. A process for preparing amorphous rimonabant comprising the steps of:
a) suspending/dissolving any other crystalline form of rimonabant in a
suitable solvent for a period of time sufficient to convert the other form into
amorphous rimonabant and
b) isolating amorphous rimonabant from the suspension.
5. The process of claim 4 wherein the solvent is selected from the group
consisting of cyclic ethers, halogcnated hydrocarbon, alkyl nitrilcs. a C3-6,
alkyl ketones, aromatic hydrocarbon, and mixtures thereof.
6. The process of claim 4 wherein the solvent is preferably selected from the
group consisting of tetrahydrofuran. dichloromelhane, chloroform,
acetonitrile. acetone, toluene and mixtures thereof,
7. The process of claim 4 wherein amorphous rimonabant is recovered from the
suspension by vacuum distillation at a temperature of 35-60°C.
8. A process for preparing form 1 of rimonabant comprising the steps of:
a) suspending amorphous rimonabant in a suitable solvent for a period of time
sufficient to convert the other form into rimonabant to form I and
b) isolating form I of rimonabant from the suspension.

9. The process of claim 8 wherein the solvent is selected from the group
consisting of aliphatic hydrocarbons, ethers, water and mixtures thereof.
10. The process of claim 8 further comprises recovering form 1 of rimonabant
from the suspension by filtering the crystals, optionally washing with solvent
and drying the crystals at 40-60°C.